The opioid system modulates several physiological processes including analgesia, stress responses, immune responses, respiration, and neuroendocrine function (Herz, Opioids 1993, Vol. 1, Springer-Verlag, Berlin). Pharmacological and molecular cloning studies have identified four opioid receptor types (mu, delta, kappa, and ORL-1) that mediate these diverse effects (Miotto et al., The Pharmacology of Opioid Peptides (Ed. L. Tseng) 1995, 57-71, Harwood Acad. Publishers; Kieffer et al., Cell Mol. Neurobiol. 1995, 15:615-35). The opioid receptors are known to couple with pertussis toxin sensitive G-proteins to modulate adenylyl cyclase activity and potassium and calcium channel currents (Handbook of Experimental Pharmacology, Vol.104/I:Opioids I (Herz, A; Ed.) 1993, Springer-Verlag, Berlin; Duggan and North, Pharm. Rev. 1983, 35:219-282).
Most clinically used opiates are mu (μ) receptor ligands. For example, β-endorphins and enkephalins are endogenous ligands for the μ receptor. Dynorphin A also has high affinity for μ receptors, but has a higher affinity for kappa (κ) receptors (see below). Morphine and other morphine-like agonists produce analgesia primarily through interaction with μ receptors. Other physiological effects that are associated with μ receptor activation include, but are not limited to, respiratory depression, miosis, reduced gastrointestinal motility, and euphoria (Parternak, Clin. Neuropharmacol 1993, 16:1-18). In situ hybridization studies have shown that μ receptor mRNA is present in brain regions associated with pain perception (e.g., periaqueductal gray, spinal trigeminal nucleus, cunate and gracile nuclei, and thalamus), respiration (e.g., nucleus of the solitary tract, nucleus ambiguus, and parabrachial nucleus), and nausea and vomiting (e.g., neurons of the area postrema) (The Pharmacological Basis of Therapeutics, 9th edition (Eds Hardman, J G and Limbird, L E) 1996 McGraw-Hill, N.Y.). It is hypothesized that addiction to morphine and analgesics occurs through hyperactivation of μ receptors.
Subclasses of the κ receptor have been identified. In situ hybridization studies show that the κ1 receptor subtype is predominantly present in hypothalamic regions, which accounts for receptor effects on neuroendocrine systems. Spinal activation of the κ1 receptor subtype elicits analgesia in animal models. κ3 receptor activation is also associated with analgesia, however it has been shown to produce its effects through supraspinal mechanisms (Clark, et al., J. Pharmacol. Exp. Ther. 1989, 251:461-468; Paul, et al., J. Pharmacol. Exp. Ther. 1991, 257:1-7). The κ2 receptor subtype was identified based on binding studies, but the pharmacological effects of this receptor are currently unknown. Selective κ receptor ligands can induce analgesia that is undiminished by μ receptor tolerance. These ligands produce a majority of the observed pharmacological and physiological effects in the spinal cord and produce less intense respiratory depression than μ agonists. κ receptor agonists also produce neuroendocrine effects and dysphoric, psychomimetic effects (Pheiffer, A. et al., Science 1986, 233:744-746).
Two subclasses of the delta (δ) receptor have been identified, δ1and δ2, based primarily on differential sensitivity to antagonists. Activation of these receptors produces analgesic effects through spinal and supraspinal mechanisms, although the spinal mechanism appears to be more robust. Activation of these receptors also produces positive reinforcing effects at supraspinal sites and antinociception for thermal stimuli at spinal sites (Pasternak, Clin. Neuropharmacol, 1993, 16:1-18). In situ hybridization studies have shown that the δ receptor is localized in the dorsal horn of the spinal cord.
A number of studies have demonstrated a broad spectrum of physiological functions of the ORL-1 receptor in both the central and peripheral nervous systems and in non-neuronal tissues. These functions include modulation of nociception (Meunier et al, Nature 1995, 377:532-5; Reinscheid et al., Science 1995, 270:792-794; Tian, et al., Br J Pharmacol 1998, 124:21-6), locomotor activity (Reinscheid et al., Science 1995, 270:792-794), reversal of stress-induced analgesia (Mogil, et al., Neuroscience 1996, 75:333-7), attenuation of stress responses (Jenck, et al., Proc Natl Acad Sci USA 1997, 94:14854-8), modulation of learning and memory (Mamiya, et al., Brain Res. 1998, 783:236-40; Manabe, et al., Nature 1998, 394:577-81; Sandin, et al., Eur J Neurosci 1997, 9:194-7), regulation of neurotransmitter and hormone release (Bryant, et al., Brain Res 1998, 807:228-33; Murphy, et al., Neuroscience 1996, 75:1-4), modulation of kidney function (Kapusta, et al., Life Sci 1997, 60:L15-21), and a potential role in neuronal differentiation (Buzas, et al., J Neurochem 1999, 72:1882-9; Saito, et al., Biochem Biophys Res Commun 1995, 217:539-45; Saito, et al., J Bio Chem 1996, 271:15615-22).
There is a continuing need in the art to develop ligands that are highly selective for one opioid receptor versus another. Development of such ligands will allow for further understanding of the pharmacology of these receptors. Additionally, such selective ligands may represent novel drugs for the treatment of pain, cough, and/or addiction that minimize adverse effects due to interaction with other opioid receptors.